Modulation of vascular function by perivascular adipose tissue: the role of endothelium and hydrogen peroxide

Abstract

Background and purpose: Perivascular adipose tissue (PVAT) attenuates vascular contraction, but the mechanisms remain largely unknown. The possible involvement of endothelium (E) and hydrogen peroxide (H 2 O 2) was investigated. Experimental approach: Aortic rings from Wistar rats were prepared with both PVAT and E intact (PVAT+E+), with either PVAT or E removed (PVAT‐E+, or PVAT+E‐), or with both removed (PVAT‐E‐) for functional studies. Nitric oxide (NO) production was measured. Key results: Contraction to phenylephrine and 5‐HT respectively was highest in PVAT‐E‐, lowest in PVAT+E+, and intermediate in PVAT+E‐ or PVAT‐E+. In bioassay experiments, transferring bathing solution incubated with a PVAT+ ring (donor) to a PVAT‐ ring (recipient) induced relaxation in the recipient. This relaxation was abolished by E removal, NO synthase inhibition, scavenging of NO, high extracellular K+, or blockade of calcium‐dependent K+ channels (K Ca). The solution stimulated NO production in isolated endothelial cells and in PVAT‐E+ rings. In E‐ rings, the contraction to phenylephrine of PVAT+ rings but not PVAT‐ rings was enhanced by catalase or soluble guanylyl cyclase (sGC) inhibitor, but reduced by superoxide dismutase and tiron. In PVAT‐E‐ rings, H 2 O 2 attenuated phenylephrine‐induced contraction. This effect was counteracted by sGC inhibition. NO donor and H 2 O 2 exhibited additive inhibition of the contraction to phenylephrine in PVAT‐E‐ rings. Conclusion: PVAT exerts its anti‐contractile effects through two distinct mechanisms: (1) by releasing a transferable relaxing factor which induces endothelium‐dependent relaxation through NO release and subsequent K Ca channel activation, and (2) by an endothelium‐independent mechanism involving H 2 O 2 and subsequent activation of sGC. British Journal of Pharmacology (2007) 151, 323–331; doi:10.1038/sj.bjp.0707228